TDP-43 stabilizes <i>G3BP1</i> mRNA: relevance to amyotrophic lateral sclerosis/frontotemporal dementia
Hadjara Sidibé, Yousra Khalfallah, Shangxi Xiao, Nicolás Gómez, Hana Fakim, Elizabeth M.H. Tank, Geneviève Di Tomasso, Eric Bareke, Anaïs Aulas, Paul M. McKeever, Ze’ev Melamed, Laurie Destroimaisons, Jade-Emmanuelle Deshaies, Lorne Zinman, Jennifer Parker, Pascale Legault, Martine Tétreault, Sami J. Barmada, Janice Robertson, Christine Vande Velde
Abstract
TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3' untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.